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Highlight • The overall response rate for steroid-refractory aGVHD at 6 to 10 weeks after vedolizumab initiation was 64%. • Overall survival at 6 months after vedolizumab initiation was 54%. • Vedolizumab therapy was not associated with significant unexpected toxicities. ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in patients with hematologic malignancies but carries a significant risk of graft-versus-host disease (GVHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GVHD (aGVHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treating SR GI aGVHD. Data were collected from patients' medical records; criteria for extraction included no more than 1 allo-HCT and at least 1 dose of vedolizumab as treatment for SR GI aGVHD (ie, stage 1 to 4 GI aGVHD following ≥1 previous treatment regimen(s) containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites who had received 1 to 10 doses of vedolizumab 300 mg i.v. (median 3 doses) as treatment for SR GI aGVHD. The overall response rate at 6 to 10 weeks after vedolizumab initiation was 64%, and OS at 6 months was 54%. There were 29 SAEs, including 12 infections; 3 SAEs were considered possibly related to vedolizumab, 2 of which were infections. Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 nonserious infections and 1 serious infection with confirmed GI origin in 8 patients; there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting from prospective trials are needed. Graphical abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]

Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin α4β7, in 6 patients. All patients responded, and 4 of 6 patients are alive with a median follow-up of 10 months. [ABSTRACT FROM AUTHOR]

There is a well-known association in male patients between mediastinal germ cell tumors (GCT) and hematologic malignancies, with a propensity towards acute megakaryoblastic leukemia. These rare malignancies have been shown to share a common clonal origin, often deduced from the finding of isochromosome 12p, i(12p), in cells from both the solid tumor and the leukemia, and thus are now known to represent different manifestations of the same clonal process. We treated a young female patient with a malignant phyllodes tumor followed by an acute megakaryoblastic leukemia and found several of the same marker chromosomes by karyotype analysis of cells from both the tumor and the leukemia implying a common clonal origin of the two. To the best of our knowledge, this has not been demonstrated in phyllodes tumors before, but indicates that the same type of leukemization may occur of this tumor as has been described in mediastinal GCT. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 34-year old female patient diagnosed with antiphospholipid syndrome (APS) following several miscarriages and deep venous thrombosis. Biochemistry indicated anemia, thrombocytopaenia and positive lupus anticoagulant. Her condition deteriorated with respiratory distress, circulatory collapse and cardiac arrest. She was started with eculizumab treatment with remarkable clinical improvements within hours.

The effects of immunostimulatory RNAs (isRNAs) on the expression of immuno-suppressive factors are largely unknown. Indoleamine 2,3-dioxygenase (IDO) is a key negative regulator of immune responses and it has been implicated in hampering immunity against tumours. Here we show that the activation of Toll-like receptors (TLR)-7/8 with isRNAs or R848, a specific ligand for TLR7/8, can induce IDO expression in human monocytes, but not in monocyte-derived dendritic cells (moDC). In contrast to TLR7/8 agnosists, treatment of the same moDC with interferon-γ-induced IDO expression. Treatment of monocytes with 2′- O-methyl uridine-modified isRNAs alone does not induce IDO, but totally abrogated the effects of unmodified isRNAs. Like isRNAs, synthetic viral RNAs and cytomegalovirus (CMV) induced IDO in monocytes, whereas TLR2 ligand lipopeptide Pam3Cys exhibited no effect. Furthermore, IDO positive monocytes suppressed autologous T-cell activation. Collectively, these data indicate for first time that the potency of TLR7/8 signalling pathways to induce IDO expression in monocytes is silenced when the cells are programmed to differentiate into dendritic cells. The immunosuppressive properties of IDO might confer an advantage to CMV-infected monocytes to escape T-cell responses. The findings that 2′- O-methyl modified RNAs can block isRNA-induced IDO expression would facilitate the design of new TLR inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Toll-like receptors (TLRs) play a key role in pathogen recognition and regulation of the innate and adaptive immune responses. Although TLR expression and signaling have been investigated in blood cells, it is currently unknown whether their bone marrow ancestors express TLRs and respond to their ligands. Here we found that TLRs (e.g. TLR4, TLR7 and TLR8) were expressed by freshly isolated human bone marrow (BM) hematopoietic CD34+ progenitor cells. Incubation of these primitive cells with TLR ligands such as immunostimulatory small interfering RNAs and R848, a specific ligand for TLR7/8, induced cytokine production (e.g. IL1-β, IL6, IL8, TNF-α, GM-CSF). Moreover, TLR7/8 signaling induced the differentiation of BM CD34+ progenitors into cells with the morphology of macrophages and monocytic dendritic precursors characterized by the expression of CD13, CD14 and/or CD11c markers. By contrast, R848 ligand did not induce the expression of glycophorin A, an early marker for erythropoiesis. Collectively, the data indicate for the first time that human BM CD34+ progenitor cells constitutively express functional TLR7/TLR8, whose ligation can induce leukopoiesis without the addition of any exogenous cytokines. Thus, TLR signaling may regulate BM cell development in humans. [Copyright &y& Elsevier]

The article presents a case study of a 58-year-old male presented with polyarthritis and cryoglobulinemia type II. Diagnosis revealed monoclonal gammopathy and chronic lymphocytic leukemia (CLL). The article discusses a case of Richter syndrome (RS) which represents a solitary central nervous system (CNS) disease. It notes that both are features are correlated with a decrease likelihood or Richter transformation.

A pilot study conducted in Ontario, Canada, evaluated the safety and effectiveness of placental decidual stromal cells (DSC) in treating severe acute respiratory distress syndrome (ARDS) caused by COVID-19. The study included 19 adult patients with COVID-ARDS who received DSC treatment. The results showed that DSC administration appeared safe, with one patient experiencing a transient hypoxic event related to the infusion. Survival to hospital discharge was significantly higher in the DSC group compared to a control group, and there was a trend towards increased survival to discharge from the intensive care unit. The study supports further evaluation of DSCs in larger, randomized, controlled trials to establish their safety and efficacy in treating severe ARDS. [Extracted from the article]

Neurologic complications are common after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and affect 30-60% of transplant recipients. The aim of this article is to provide a practical imaging approach based on the timeline and etiology of CNS abnormalities, and neurologic complications related to transplantation of specific organs. The lesions will be classified based upon the interval from HSCT procedure: pre-engraftment period <30 days, early post-engraftment period 30-100 days, late post-engraftment period >100 days, and the interval from SOT procedure: postoperative phase 1-4 weeks, early posttransplant syndromes 1-6 months, late posttransplant syndromes >6 months. Further differentiation will be based on etiology: infections, drug toxicity, metabolic derangements, cerebrovascular complications, and posttransplantation malignancies. In addition, differentiation will be based on complications specific to the type of transplantation: allogeneic and autologous hematopoietic stem cells (HSC), heart, lung, kidney, pancreas, and liver. Thus, in this article we emphasize the strategic role of neuroradiology in the diagnosis and response to treatment by utilizing a methodical approach in the work up of patients with neurologic complications after transplantation. [ABSTRACT FROM AUTHOR]

Purpose: GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype–phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT. Methods: All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records. Results: Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype–phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively. Conclusion: Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described. [ABSTRACT FROM AUTHOR]

Good's syndrome is a rare acquired immunodeficiency associated with thymoma. Eltrombopag is a thrombopoietin receptor agonist and has been shown to be a valuable supplement to the treatment of several types of refractory cytopenias. In this paper, we describe a male patient suffering from Good's syndrome with immune-mediated T-cell driven pancytopenia and absence of megakaryopoiesis. He was successfully treated with eltrombopag resulting in a multilineage clinical response. [ABSTRACT FROM AUTHOR]

Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. Chow diet-fed atherosclerosis-prone Apoe −/− mice deficient in Neil3 , and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway. [Display omitted] • Apoe−/−/Neil3−/− mice develop more atherosclerosis as compared to Apoe−/− mice. • Apoe−/−/Neil3−/− mice display increased medial VSMC area and layer disorganization. • Increased aortic VSMC proliferation in Apoe −/− /Neil3 −/− mice and NEIL3-deficient primary human VSMCs. • Neil3 deficiency increases aortic VSMC phenotypic transdifferentiation towards an atherosclerotic macrophage-like cells. • Neil3/NEIL3 deficiency-dependent VSMC proliferation involves activation of the Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Breakpoint Cluster Region-Abelson kinase (BCR-Abl) is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells (LSCs), the cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. New strategies to target cancers driven by BCR-Abl are therefore urgently needed. We performed a small molecule screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells and identified several compounds that selectively impair the fitness of BCR-Abl-transformed cells. Interestingly, systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. DJ34-mediated c-Myc depletion occurred in a wide range of tumor cell types, including lymphoma, lung, glioblastoma, breast cancer, and several forms of leukemia, with primary LSCs being particularly sensitive to DJ34. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest, and cell differentiation. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against LSCs. [ABSTRACT FROM AUTHOR]

Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor The early mortality (EM) in acute myeloid leukaemia (AML) is a significant clinical problem in AML management. Palliative patients were to a larger extent female, older, with more secondary AML, higher cytogenetic high risk and higher PS compared to induction patients ( I P i -values: 0-003, <0-001, <0-001, <0-001 and <0-001 respectively) (see Table). Again, when applying the adjusted model the improving trend of EM was abrogated among the intensively treated patients [RR = 1-00(95% CI: 0-97-1-02), I P i = 0-807] (Fig C), while for palliative patients the adjusted EM risk actually increased from the reference year 1997 [RR = 1-02(95% CI: 1-01-1-03), I P i = 0-001] (Fig B). [Extracted from the article]

Heme is a critical danger molecule liberated from hemeproteins in various conditions, including from hemoglobin in hemolytic diseases. Heme may cause thromboinflammatory damage by activating inflammatory and hemostatic pathways, such as complement, the TLRs, coagulation, and platelets. In this study, we explored the effect of single and dual inhibition of complement component C5 and TLR coreceptor CD14 on heme-induced thromboinflammation in an ex vivo human whole blood model. Heme induced a dose-dependent activation of complement via the alternative pathway. Single inhibition of C5 by eculizumab attenuated the release of IL-6, IL-8, TNF, MCP-1, MIP-1α, IFN-γ, LTB-4, MMP-8 and -9, and IL-1Ra with more than 60% (p < 0.05 for all) reduced the upregulation of CD11b on granulocytes and monocytes by 59 and 40%, respectively (p < 0.05), and attenuated monocytic tissue factor expression by 33% (p < 0.001). Blocking CD14 attenuated IL-6 and TNF by more than 50% (p < 0.05). In contrast to single inhibition, combined C5 and CD14 was required for a significantly attenuated prothrombin cleavage (72%, p < 0.05). Markers of thromboinflammation were also quantified in two patients admitted to the hospital with sickle cell disease (SCD) crisis. Both SCD patients had pronounced hemolysis and depleted plasma hemopexin and haptoglobin. Plasma heme and complement activation was markedly increased in one patient, a coinciding observation as demonstrated ex vivo. In conclusion, heme-induced thromboinflammation was largely attenuated by C5 inhibition alone, with a beneficial effect of adding a CD14 inhibitor to attenuate prothrombin activation. Targeting C5 has the potential to reduce thromboinflammation in SCD crisis patients. [ABSTRACT FROM AUTHOR]

mAbs have emerged as a promising strategy for the treatment of cancer. However, in several malignancies, no effective antitumor mAbs are yet available. Identifying therapeutic mAbs that recognize common tumor antigens could render the treatment widely applicable. Here, a human single-chain variable fragment (scFv) antibody library was sequentially affinity selected against a panel of human cancer cell lines and an antibody fragment (named MS5) that bound to solid and blood cancer cells was identified. The MS5 scFv was fused to the human IgG1 Fc domain to generate an antibody (MS5-Fc fusion) that induced antibody-dependent cellular cytotoxicity and phagocytosis of cancer cells by macrophages. In addition, the MS5-Fc antibody bound to primary leukemia cells and induced antibody-dependent cellular cytotoxicity. In the majority of analyzed cancer cells, the MS5-Fc antibody induced cell surface redistribution of the receptor complexes, but not internalization, thus maximizing the accessibility of the IgG1 Fc domain to immune effector cells. In vitro stability studies showed that the MS5-Fc antibody was stable after 6 d of incubation in human serum, retaining ~60% of its initial intact form. After intravenous injections, the antibody localized into tumor tissues and inhibited the growth of 3 different human tumor xenografts (breast, lymphoma, and leukemia). These antitumor effects were associated with tumor infiltration by macrophages and NK cells. In the Ramos B-cell lymphoma xenograft model, the MS5-Fc antibody exhibited a comparable antitumor effect as rituximab, a chimeric anti-CD20 IgG1 mAb. These results indicate that human antibodies with pan-cancer abilities can be generated from phage display libraries, and that the engineered MS5-Fc antibody could be an attractive agent for further clinical investigation. [ABSTRACT FROM AUTHOR]

Lesions of hyaline cartilage do not heal spontaneously, and represent a therapeutic challenge. In vitro engineering of articular cartilage using cells and biomaterials may prove to be the best solution. Patients with osteoarthritis (OA) may require tissue engineered cartilage therapy. Chondrocytes obtained from OA joints are thought to be involved in the disease process, and thus to be of insufficient quality to be used for repair strategies. Bone marrow (BM) derived mesenchymal stem cells (MSCs) from healthy donors may represent an alternative cell source. We have isolated chondrocytes from OA joints, performed cell culture expansion and tissue engineering of cartilage using a disc-shaped alginate scaffold and chondrogenic differentiation medium. We performed real-time reverse transcriptase quantitative PCR and fluorescence immunohistochemistry to evaluate mRNA and protein expression for a range of molecules involved in chondrogenesis and OA pathogenesis. Results were compared with those obtained by using BM-MSCs in an identical tissue engineering strategy. Finally the two populations were compared using genome-wide mRNA arrays. At three weeks of chondrogenic differentiation we found high and similar levels of hyaline cartilage-specific type II collagen and fibrocartilage-specific type I collagen mRNA and protein in discs containing OA and BM-MSC derived chondrocytes. Aggrecan, the dominant proteoglycan in hyaline cartilage, was more abundantly distributed in the OA chondrocyte extracellular matrix. OA chondrocytes expressed higher mRNA levels also of other hyaline extracellular matrix components. Surprisingly BM-MSC derived chondrocytes expressed higher mRNA levels of OA markers such as COL10A1, SSP1 (osteopontin), ALPL, BMP2, VEGFA, PTGES, IHH, and WNT genes, but lower levels of MMP3 and S100A4. Based on the results presented here, OA chondrocytes may be suitable for tissue engineering of articular cartilage. [ABSTRACT FROM AUTHOR]

Objective. Phenotypical changes in the human bone marrow (BM) due to age and stress have not so far been properly addressed in the literature. In the present study, we compared CD34+ BM cells between older and young volunteers. The influence of stress on CD34+ cell phenotype in older patients was investigated in an age-matched group with acute myocardial infarction (AMI). Cytokines thought to influence BM CD34+ cell homeostasis were also analysed. Material and methods. BM mononuclear cells of 10 older volunteers and of 7 young volunteers (18-25 years), as well as 22 AMI patients, were analysed by flow cytometry for the following markers: CD34, CD38, CD117 (c-kit) and CD133. Blood samples were analysed for CRP, IL-6, MCP-1, IL-8, MMP-9, TIMP-1 and TNFα by ELISA methods. Results. Significantly higher numbers of CD34+ CD38- cells (both absolute and relative) were observed in older volunteers than in young volunteers and AMI patients. Higher numbers of immature progenitors, namely CD34+CD38- cells and CD34+CD38-CD117+CD133+ cells, were observed among older volunteers compared to the other groups. However, the relative number of CD34+ cells lacking CD38 expression or expressing CD133 was higher in the old volunteers and AMI patients. None of the circulating factors investigated correlated with any of the cell population yields. Conclusion. In this study, we found that the absolute and relative numbers of BM CD34+CD38- progenitor cells increase with age. The increment is attenuated in patients with AMI. [ABSTRACT FROM AUTHOR]

Several cells of myeloid origin, such as monocytes and macrophages are involved in various human disorders, including cancer and inflammatory diseases. Hence, they represent attractive therapeutic targets. Here we developed three lytic hybrid peptides, by fusing a monocyte- and macrophage-binding peptide to pro-apoptotic peptides, and investigated their killing potency on blood monocytes, macrophages, and leukemia cells. We first showed that the targeting NW peptide is effective for depleting monocytes from whole peripheral blood mononuclear cells (PBMCs). Incubating the cells with biotin-conjugated NW peptide, and the subsequent capture on streptavidin-conjugated magnetic beads, depleted monocytes from the PBMCs. The NW peptide also depleted myeloid leukemia blasts from patient PBMCs. The treatment of the PBMCs with the lytic hybrid NW-KLA peptide killed monocytes, but not lymphocytes and primary mammary epithelial cells. Additionally, the fusion peptide exhibited a potent toxicity against macrophages and leukemia cells. The free lytic KLA peptide did not affect cells. Similarly, a second lytic hybrid peptide killed macrophages, leukemia cell lines, and blood leukemia blasts from patients with acute and chronic myeloid leukemia. The IC50 towards target cells were in the low macromolar range (4–12 µM). Overall, the data indicate that the NW peptide could be a potential drug delivery agent for monocytes, macrophages, and leukemia cells. Moreover, the engineered lytic hybrid peptides acting alone, or in combination with other therapeutic agents, might benefit many cancer patients and overcome drug resistance. [ABSTRACT FROM AUTHOR]